1. Field of the Invention
The present invention is broadly directed to a method of inhibiting or decreasing vascular permeability associated with dermal edema, e.g., induration, and especially the increased vascular permeability induced by vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF). The present invention is particularly directed to the use of Protein Kinase C (PKC) inhibitors, especially a particular class of isozyme selective PKC inhibitors for treating bullous phemigoid, erythema multiforme, dermatitis herpetiformis, contact dermatitis/delayed hypersensitivity, and allergic skin conditions.
2. Description of Related Art
Dermatological disorders such as bullous phemigoid, erythema multiforme, dermatitis herpetiformis, contact dermatitis, and allergic skin conditions are characterized by dermal edema. Bullous pemphigoid usually occurs in the elderly and may affect any of or all the skin and mucosal surfaces. Dermatitis herpetiformis is characterized by intensely pruritic, grouped vesicles which tend to be symmetrically distributed on the extensor surfaces of the limbs and over the scalp, buttocks, and back.
Erythema multiforme syndrome is a characteristic response of the skin and mucous membranes that is related to a number of possible etiologies, including infectious agents (herpesvirus hominis, Mycoplasma pneumoniae) and drugs (especially penicillin, antipyretics, barbiturates, hydantoins, and sulfonamides). In 50 percent of patients no etiology is ascertained. The major pathologic change in erythema multiforme is an acute lymphohistiocytic inflammatory infiltrate around blood vessels and may include degenerative changes in the endothelial cells of the capillaries and marked papillary dermal edema. The lesions occur in a characteristic symmetrical distribution and the syndrome may also include severe toxemia and prostration, high fever, cough, and "patchy" inflammation of the lungs.
Contact dermatitis/delayed hypersensitivity is a dermatological condition that is characterized by red indurated cutaneous lesions occurring hours to days after exposure to a sensitizing agent. Poison ivy is one of the common sensitizing agents to cause such skin condition.
These skin conditions are associated with vascular hyperpermeability and dermal edema (Macvicar D, et al, 1963; J Invest Dermatol 41:289; Pierard J and Whimster L 1961; Br J Dermatol 73:253). Hyperpermeability of the surrounding microvasculature is a constant feature of contact dermatitis/delayed hypersensitivity (Voisin et al, Ann. Inst. Pasteur. 104: 169, 1963). Recent studies have implicated VPF/VEGF in the formation of the dermal edema and subepidermal bullae formation (Brown L, et al, 1995; J Invest Dermatol 104:744). Recent investigations have demonstrated the presence of VPF/VEGF in monocytes/macrophages and keratinocytes in experimental models of contact dermatitis/delayed hypersensitivity reactions (Brown et al., J Immunol. 154: 2801, 1995). VEGF levels are significantly increased in skin lesions manifesting the disease entities described above. In particular, patients with the aforementioned skin lesions display extremely high levels of VEGF in the bullae of these lesions. Therapeutic treatments such as corticosteroids, and sulfone or sulfapyridine therapy have been developed over the years to treat these blistering disorders. However, there is still a need in the art to develop new therapeutic agents for skin lesion treatment, especially therapeutic agents targeted at the VPF/VEGF stimulated vascular permeability.